Preventing relapse is a major goal for the treatment of drug addiction. One precipitating factor for relapse is exposure to drug-associated environmental stimuli. The aim of the current application is to investigate novel means for reducing the relapse-triggering power of cocaine-associated stimuli. Our approach is to enhance the learning that occurs during extinction training with the aim that this will decrease the susceptibility to future recovery of the extinguished cocaine-seeking behavior. Specifically, the studies within the current application will use an animal model of relapse to test the hypothesis that deepening the extinction of cocaine-related stimuli can reduce the future ability of these stimuli to produce cocaine-seeking behavior. These studies will capitalize on recent behavioral studies that suggest that presenting reward-related stimuli together, in compound, during extinction will enhance the effectiveness of the extinction training. Therefore, the studies in Aim 1 will test the role of stimulus compounding during extinction on later cue-induced reinstatement and spontaneous recovery of cocaine-seeking by rats. There is also exciting evidence that reward-related stimuli can activate the norepinephrine (NE) system, and that activation of the norepinephrine system may enhance extinction learning. Based on these findings, we will investigate the effects of increasing or decreasing the activity of the norepinephrine system during extinction learning and assess the impact on later cocaine-seeking behavior. These effects will be tested in cue-induced reinstatement in studies in Aim 2. Because there is a need for human addicts to resist the tendency to relapse for extended time periods after treatment, we will also examine the extent to which enhanced extinction learning resulting from activation of the norepinephrine system will withstand the passage of time using tests of spontaneous recovery in studies in Aim 3. The overall hypothesis guiding this work is that the presentation of excitatory stimuli during extinction engages noradrenergic systems that serve to enhance extinction learning, and therefore manipulation of stimulus presentation during extinction learning, or direct pharmacological manipulation of NE during extinction learning, will promote extinction learning. Hence we will use both behavioral and pharmacological approaches to enhance extinction of drug-seeking responses, thereby reducing later drug-seeking. It is anticipated that these initial studies conducted under the R03 mechanism will provide the basis for future in-depth research applications investigating the detailed neural bases of observed positive effects. The overall goal is to find ways to strengthen extinction of cocaine-seeking to reduce the likelihood of future relapse. By determining behavioral and pharmacological ways to enhance the stability and longevity of extinction learning, we hope to provide insight into the development of new therapies for drug addiction that will be less susceptible to relapse. [unreadable] [unreadable] [unreadable]